肝窦内皮细胞（LSECs）是肝脏门户，它们的病理性血管生成通过影响肝组织修复和炎症驱动在肝纤维化的发病机制中扮演着积极的角色。虽然干预血管生成可以有效抑制LSEC的异常激活，但尚未发现有效的药物治疗肝纤维化。我们研究了天然化合物Curcumol对LSEC血管生成的影响，并阐明了其新颖的潜在机制，期望为探索治疗肝纤维化的潜在药物提供科学依据。我们使用各种细胞和分子生物学方法以及基因分析技术检测培养的大鼠LSEC和小鼠肝纤维化模型中的病理性血管生成和糖酵解水平的变化。转录因子KLF5能够通过调节糖酵解过程影响LSEC的血管生成特性，并通过转录结合其启动子影响LDH-A的表达。在我们的研究中，我们惊奇地发现LDH-A（糖酵解的最终步骤）对LSEC的糖酵解过程具有强烈的调节作用。通过深入研究，我们发现LDH-A可以影响KLF5的转录活性，从而形成一个正反馈环路。Curcumol可以打破这个正反馈环路，抑制LSEC的糖酵解依赖性血管生成特性，从而缓解肝纤维化。Curcumol减少了细胞外基质（ECM）沉积，减弱了LSEC的病理性血管生成，并降低了CCl4诱导小鼠肝纤维化的水平。我们的研究结果展示了KLF5在肝纤维化中的巨大应用价值，还揭示了LDH-A通过施加非酶作用来调节糖酵解过程并形成恶性反馈环路的创新性发现。它还揭示了Curcumol调节KLF5/LDH-A正反馈环路治疗肝纤维化的前景，为未来的肝纤维化医学提供了一个新的选择。版权所有© 2023 Elsevier GmbH出版。

LSECs (Liver sinusoidal endothelial cells) are the portal of liver, their pathological angiogenesis plays a constructive role in etiopathogenesis of liver fibrosis by affecting liver tissue repair and inflammatory drive. Although intervention in angiogenesis can effectively inhibit abnormal activation of LSEC, no effective drugs have been found to treat liver fibrosis.We investigated the effect of the natural compound Curcumol on LSEC angiogenesis and elucidated the novel underlying mechanism, expecting to provide a scientific basis for exploring potential therapeutic drugs for liver fibrosis.Various cellular and molecular assays, as well as genetic assays, were used to detect pathological angiogenesis and changes in glycolysis levels in cultured rat LSECs and mouse liver fibrosis models.Transcription factor KLF5 is able to influence the angiogenic properties of LSEC by regulating the glycolytic process, and affect the expression of LDH-A by transcriptionally binding to its promoter. In our study, we were surprised to find that LDH-A (the final step of glycolysis) has a strong regulatory effect on the glycolytic process of LSEC. Through in-depth study, we found that LDH-A could affect the transcriptional activity of KLF5, thus forming a positive feedback loop. Curcumol could break this positive feedback loop and inhibit the glycolysis-dependent angiogenic nature of LSEC, thus alleviating liver fibrosis. Curcumol reduced extracellular matrix (ECM) deposition, attenuated pathological angiogenesis in LSEC, and decreased the level of CCl4-induced liver fibrosis in mice.Our results demonstrated the great utilization potentiality of KLF5 in liver fibrosis, and the innovative discovery that LDH-A regulates the glycolytic process and forms a malignant feedback loop by exerting non-enzymatic effects. It also reveals the prospect of Curcumol-regulated KLF5/LDH-A feedback loop in the treatment of liver fibrosis, providing a new option for the future medicine of liver fibrosis.Copyright © 2023. Published by Elsevier GmbH.